Spondyloarthritis can be considered one of the prototypes (besides rheumatoid arthritis) of an inflammatory rheumatic disease. The locomotor system is prominently involved with arthritis, enthesitis, dactylitis, sacroiliitis, and/or axial disease; but besides the rheumatologic component, other body systems are frequently affected. Extra-articular manifestations are all the medical conditions and symptoms that are not directly related to the locomotor system. Besides inflammatory bowel diseases, the major concept-related extra-articular manifestations are located in the eye (acute anterior uveitis) and the skin (psoriasis). This review focuses on the possible implications of these nonrheumatologic manifestations regarding the treatment of spondyloarthritis.
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IBD, psoriasis and uveitis are typical spondyloarthritis concept-related extra-articular manifestations.
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Although frequently prescribed, limited evidence-based data on the efficacy of conventional DMARDS such as sulphasalazine, methotrexate and cyclosporin on extra-articular manifestations are available.
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Besides the well-established beneficial effects on rheumatological manifestations, biologics targeting TNF-alpha also have an impact on the extra-articular manifestations with a potential more profound efficacy of monoclonal antibodies versus soluble receptor constructs.
Introduction
Spondyloarthritis (SpA) can be considered one of the prototypes (besides rheumatoid arthritis) of an inflammatory rheumatic disease. The locomotor system is, of course, prominently involved with arthritis, enthesitis, dactylitis, sacroiliitis, and/or axial disease; but besides the rheumatologic component, other body systems are frequently affected. The authors’ consider extra-articular manifestations all the medical conditions and symptoms that are not directly related to the locomotor system. SpA is now classified according to its predominant presenting symptom, which can be axial (encompassing forms with clear-cut radiographic involvement previously named ankylosing spondylitis [AS] as well as nonradiographic forms) or peripheral (arthritis associated with inflammatory bowel disease, some forms of psoriatic arthritis, and reactive arthritis). In SpA, extra-articular manifestations can be divided in 2 groups: those related to the SpA concept, such as involvement of the skin, eye, gut, or urogenital system, and those more reflecting chronic, longstanding inflammation, which involve the heart, lung, kidney, and nerves. The concept-related manifestations are relatively frequent (20%–60%), can occur at any moment of the disease evolution (sometimes as the first manifestation), and can sometimes be related to axial or peripheral joint inflammation. Many studies have found higher incidences of extra-articular manifestations to be a consequence of uncontrolled systemic inflammation. Besides inflammatory bowel diseases, such as Crohn disease and ulcerative colitis, which is dealt by Jacques P and colleagues, with in a separate article in this issue, the major concept-related extra-articular manifestations are located in the eye (acute anterior uveitis) and the skin (psoriasis). This review focuses on the possible implications of these nonrheumatologic manifestations with regard to the treatment of SpA.
Acute anterior uveitis
Acute anterior uveitis (AAU) is the most common form of uveitis, with an annual incidence rate of about 8 cases per 100 000 population. Although anterior uveitis is usually the most easily managed form of uveitis, recurrences may result in severe visual loss. The disease primarily affects only the anterior chamber of the eye. A typical attack has a sudden onset and is unilateral (but in subsequent attacks the other eye may be involved); local redness, pain, photophobia, and reduced vision are the cardinal symptoms. An attack usually lasts up to 6 to 12 weeks. In most cases, local treatment is sufficient; however, relapses are frequent. Prolonged, uncontrolled anterior uveitis can extend into the posterior part of the eye with the formation of synechiae and secondary glaucoma. From an ophthalmologic point of view, it can be a significant cause of vision loss. AAU is a prominent manifestation of spondyloarthritides with a strong link with human leukocyte antigens (HLA) B27, occurring in 30% to 40% of patients with AS. About 50% of patients with AAU as an initial presentation have or will develop a form of SpA. Power and colleagues found that patients who are HLA-B27 positive have a more severe clinical course with a significantly higher rate of recurrent inflammatory attacks and, hence, a higher incidence of ocular complications, supporting the need for more aggressive therapeutic strategies. Banares and colleagues also described a relationship between anterior uveitis and bowel inflammation (in 60% of patients with AS-related uveitis), with a close relation between the recurrence of uveitis and the presence of chronic intestinal inflammation.
Acute anterior uveitis
Acute anterior uveitis (AAU) is the most common form of uveitis, with an annual incidence rate of about 8 cases per 100 000 population. Although anterior uveitis is usually the most easily managed form of uveitis, recurrences may result in severe visual loss. The disease primarily affects only the anterior chamber of the eye. A typical attack has a sudden onset and is unilateral (but in subsequent attacks the other eye may be involved); local redness, pain, photophobia, and reduced vision are the cardinal symptoms. An attack usually lasts up to 6 to 12 weeks. In most cases, local treatment is sufficient; however, relapses are frequent. Prolonged, uncontrolled anterior uveitis can extend into the posterior part of the eye with the formation of synechiae and secondary glaucoma. From an ophthalmologic point of view, it can be a significant cause of vision loss. AAU is a prominent manifestation of spondyloarthritides with a strong link with human leukocyte antigens (HLA) B27, occurring in 30% to 40% of patients with AS. About 50% of patients with AAU as an initial presentation have or will develop a form of SpA. Power and colleagues found that patients who are HLA-B27 positive have a more severe clinical course with a significantly higher rate of recurrent inflammatory attacks and, hence, a higher incidence of ocular complications, supporting the need for more aggressive therapeutic strategies. Banares and colleagues also described a relationship between anterior uveitis and bowel inflammation (in 60% of patients with AS-related uveitis), with a close relation between the recurrence of uveitis and the presence of chronic intestinal inflammation.
Psoriasis
Psoriasis is a chronic, autoimmune, inflammatory skin disorder affecting about 2% of the Caucasian population. In Europe, it is estimated to affect 5.1 million people. The most common form of psoriasis is plaque psoriasis, which occurs in approximately 80% of all patients with psoriasis. Some patients with psoriasis develop a specific form of inflammatory arthritis termed psoriatic arthritis (PsA), which is characterized by chronic inflammation of the joints, entheses, and spine. Although previously considered to be a relatively mild form of arthritis, there has been growing appreciation that PsA can be destructive and deforming with an indolent and progressive course. The exact prevalence of PsA in patients with psoriasis is unknown. Reported prevalences vary depending on the population studied and the method of assessment, but the true estimate is likely around 30%. The skin and nail lesions in SpA are largely identical to isolated skin disease (mostly plaque psoriasis); but the lesions are sometimes localized on more atypical localizations, such as the palms of hands and feet (palmoplantar pustulosis). There are no data supporting a parallelism between the activity of psoriasis and the locomotor inflammation.
Treatment: general principles
The individual treatment of patients with SpA is extremely challenging because of the heterogeneous character of the diseases that are part of this family of interrelated conditions. Not only is there a different therapeutic approach depending on whether the main presenting rheumatologic manifestation is back pain, arthritis, enthesitis, or dactylitis but also the presence and the extent of extra-articular manifestations significantly influences the therapeutic decisions in an individual patient. Recently, the 2010 update of the Assessment of Spondyloarthritis International Society/European League Against Rheumatism (ASAS/EULAR) recommendations for the management of AS was published. As with other guidelines, they introduced the concept of overarching principles, stating that AS is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary treatment coordinated by the rheumatologist, with the primary goal of maximization of long-term health-related quality of life through the control of symptoms and inflammation, prevention of progressive structural damage, and the preservation/normalization of function and social participation. It is explicitly stated that the treatment should be tailored according to the current manifestations of the disease (axial, peripheral, entheseal, and extra-articular symptoms and signs) as well as the level of current symptoms, clinical findings, and prognostic indicators.
The optimal management requires a combination of nonpharmacologic treatment modalities, such as patient education and regular exercise, and pharmacologic therapy. Nonsteroidal antiinflammatory drugs (NSAIDs) are recommended as the first-line drug treatment for patients with pain and stiffness. Corticosteroid injections can be directed to the local site of musculoskeletal inflammation, but the use of systemic glucocorticoids for axial disease is not supported by evidence. Likewise, there is no evidence for the efficacy of disease-modifying antirheumatic drugs (DMARDs), including sulfasalazine and methotrexate, for the treatment of axial disease, but sulfasalazine may be considered in patients with peripheral arthritis. Although again not supported by evidence, most rheumatologists will also try methotrexate in predominant peripheral spondyloarthritis. Finally, anti–tumor necrosis factor (TNF) therapy should be given to patients with persistently high disease activity despite conventional treatments. With regard to axial and articular/entheseal disease manifestations, there is no evidence for a significant difference in efficacy of the various available TNF inhibitors (infliximab, etanercept, adalimumab, golimumab). However, a specific recommendation is reserved for extra-articular manifestations and comorbidities; these frequently observed conditions, such as psoriasis, uveitis, and inflammatory bowel disease, should be managed in collaboration with the respective specialists. In these cases, a differential efficacy of the available conventional and biologic treatment modalities may play an important role. In this article, the authors review the relevance of extra-articular manifestations for therapeutic decisions, with a specific focus on the eye and the skin.
Efficacy of SpA treatments on psoriasis
Conventional Treatments
Traditional systemic treatment of psoriasis with methotrexate, retinoids, and cyclosporine has been in use for more than 20 years and still represents the first-line systemic treatment in Europe for patients with psoriasis who cannot be controlled with topical agents or phototherapy. Because of the important psoriasis burden on patient life, there is evidence of an increasing use of systemic agents in psoriasis over the past 10 years when compared with previous years. There is a high level of heterogeneity regarding the practical daily life use of conventional systemic treatments in psoriasis. Despite the fact that only a few prospective, randomized, placebo-controlled studies of the conventional systemic agents exist, recommendations have been generated to guide physicians on the best use of traditional agents in psoriasis. The authors present here an overview of the efficacy of the most commonly used treatments of SpA or PsA on psoriasis.
Nonsteroidal antiinflammatory drugs
Evidently, NSAIDs do not play a role in the treatment of skin or nail psoriasis. Drugs, such as indomethacin and ibuprofen, have occasionally been reported to exacerbate psoriasis, although additional well-controlled studies are still needed. Because psoriasis is a very complex disease and its activity is often unpredictable, clinical studies of adverse drug effects on psoriasis have been difficult to conduct.
Sulfasalazine
Evidence for the efficacy of sulfasalazine on skin psoriasis is scarce, as it was only evaluated in a small prospective, randomized, double-blind, placebo-controlled study. Twenty-three patients received active treatment (ranging from 1.5–4.0 g of daily sulfasalazine), and 6 patients discontinued because of the side effects. In the remaining 17 patients, 7 had marked (60%–89%) change and another 7 had moderate (30%–59%) improvement. The placebo arm (n = 27) had only one subject who showed moderate improvement, whereas the rest of the group had only minimal improvement or worsening of psoriasis.
Methotrexate
Dermatologists were among the first to embrace methotrexate as an antiinflammatory/immune-modulating agent, with Edmunson and Guy reporting its efficacy in the treatment of psoriasis in 1958. One of the earliest studies with methotrexate, in 50 patients, reported more than 50% improvement in psoriasis in 82% of patients. It has since been claimed that greater than 90% clearance could be achieved in 30% to 50% of patients treated aggressively with methotrexate. There are no randomized placebo-controlled trials evaluating methotrexate in patients with plaque psoriasis. Three well-designed active-comparator studies that evaluated the efficacy of methotrexate were performed in the last decade. Heydendael and colleagues compared methotrexate with cyclosporine in moderate to severe chronic plaque psoriasis; in this trial, at 16 weeks of treatment, there was no significant advantage of one drug over the other with a psoriasis area and severity (PASI) 75 response in 60% versus 71% for methotrexate and cyclosporine, respectively. Saurat and colleagues performed a double-blind placebo-controlled study of methotrexate, designed to compare the safety and efficacy of adalimumab, methotrexate, and placebo in 250 patients. After 16 weeks of treatment, PASI 75 improvement was 19% for placebo, 36% for methotrexate, and 80% for adalimumab. For those patients in the methotrexate arm of the study, methotrexate was initiated at a low weekly dosage of 7.5 mg for 2 weeks, followed by 10 mg weekly for 2 weeks, and then 15 mg for 4 weeks. Thereafter, an increase in the dosage of methotrexate was permitted depending on the response and the presence or absence of toxicity. After 8 weeks, if patients in the methotrexate arm had achieved a PASI 50 response, no further increase in the methotrexate dosage was allowed. Methotrexate seems as effective as maintenance therapy in plaque psoriasis.
Cyclosporine
Cyclosporine is a highly effective and rapidly acting systemic agent belonging to the family of immunosuppressant drugs known as calcineurin inhibitors. The original observation that cyclosporine is an effective therapy for psoriasis was the consequence of an investigation for the treatment of arthritis. Four patients in the study group had PsA; in these patients, the high doses of cyclosporine in use at that time cleared the patients of psoriasis within 2 weeks of therapy initiation. Indeed, it was this and subsequent observations in the 1980s that provided added evidence that psoriasis is a T-cell-mediated dermatosis. The only placebo-controlled analysis of cyclosporine enrolled 85 adult patients with moderate to severe psoriasis into 3 dosing arms (3.0, 5.0, and 7.5 mg/kg daily); a fourth group received placebo. Efficacy was measured after 8 weeks and quantified the patients becoming “clear or almost clear.” The analysis by intention to treat showed that cyclosporine improved psoriasis in a dose-dependent manner, with clear or almost clear results achieved by 36% in the cyclosporine 3.0 mg/kg daily group, 65% in the 5.0 mg/kg daily group, 80% in the 7.5 mg/kg daily group, and 0% in the placebo group. These results were statistically significant. Multiple other studies added to the evidence that cyclosporine given at a dosage of 3 mg/kg daily for 12 to 16 weeks leads to rapid and dramatic improvement in psoriasis with a PASI 75 response in 50% to 70% of patients and even a PASI 90 response in 30% to 50% of cases. Because of concerns of organ (renal) toxicity, cyclosporine is used mainly in short-term (12 weeks) intermittent courses.
Leflunomide
Leflunomide has demonstrated some usefulness in treating cutaneous psoriasis. One published prospective, multicenter, randomized, double-blind, placebo-controlled study showed mild efficacy for the treatment of psoriasis. In this study, 182 adult patients with psoriasis and PsA were randomized to either placebo or leflunomide given as 20 mg daily for 6 consecutive months. Patients had a baseline body surface area of psoriasis involvement that was greater than 3% and were allowed low-dose systemic corticosteroids (about 15% of the leflunomide-treated group). After 24 weeks of treatment, 17% of the leflunomide-treated patients achieved a PASI 75 versus 8% receiving placebo ( P = .048).
Although larger, prospective, well-powered, placebo-controlled studies would be useful to provide further evidence-based information on conventional treatments in psoriasis, it can be concluded from the current available literature that methotrexate is effective and well tolerated in appropriately selected patients who are adequately monitored for potential toxicities. Cyclosporine suffers from dose-related nephrotoxicity and hypertension that impede its use as a long-term agent for most patients. Given this restriction, cyclosporine is an effective drug for rapid clearing in most patients, serving as an excellent bridging agent that can be used safely for periods of 2 to 12 months. Sulfasalazine and leflunomide have poor evidence substantiating their use as monotherapy in plaque psoriasis.
Biologics
As mentioned, conventional systemic therapies for psoriasis are not effective in all patients and they may be associated with toxicities that can limit their long-term use. In recent years, biologic therapies have offered new, exciting treatment options with improved safety and efficacy for the treatment of psoriasis. The biologic therapies used in psoriasis are defined by their mode of action and can be classified into 3 categories: T-cell modulating agents (alefacept, efalizumab), agents that block TNF-alpha, and inhibitors of interleukin (IL)12/23 (ustekinumab). In clinical trials, the toxicity of biologicals has usually been mild to moderate, although severe side effects have been described. The use of a biological may be considered when patients cannot tolerate or are unresponsive to conventional systemic therapy.
T-cell modulating therapy
In 2003, alefacept and efalizumab were the first biologic agents to be approved by the Food and Drug Administration for the treatment of psoriasis. In the European Union, only efalizumab was approved for the treatment of moderate to severe plaque psoriasis. Efalizumab is a monoclonal antibody binding to the human CD11a subunit in leukocyte function antigen-1 (LFA-1), thereby blocking the binding of LFA-1 to intracellular adhesion molecule-1; this causes loss of activation, adhesion, and migration of T cells. In 2009, efalizumab was withdrawn from the market because of 3 cases of progressive multifocal leukoencephalopathy described in patients on long-term (>3 years) therapy. Alefacept, a recombinant dimeric fusion protein, is made up of the terminal portion of leukocyte function antigen-3 (LFA-3), blocking the signal between LFA-3 on antigen-presenting cells and the CD2 molecule on T cells. As a consequence, the activation and proliferation of T lymphocytes is inhibited. Using a weekly dosage of 15 mg administered intramuscularly, PASI 75 scores at week 12 were found to range between 21% and 35%. In a PsA study, alefacept in combination with methotrexate was shown to improve arthritis significantly, with 54% ACR 20 responders compared with 23% in the methotrexate-alone group ( P <.001). However, in November 2011, Astellas Pharma voluntarily withdrew alefacept from the market for business reasons.
TNF-blocking agents
The potential importance of TNF in the pathophysiology of psoriasis is underscored by the observation that there are elevated levels of this cytokine in both the affected skin and serum of patients with psoriasis. These elevated levels have a significant correlation with psoriasis severity as measured by the PASI score, and a reduction to normal levels is observed after successful treatment with TNF-blocking agents. Currently, the 4 anti-TNF agents available for the treatment of signs and symptoms of AS are also indicated for PsA, with a fifth agent, certolizumab, for which preliminary results of a phase III study were recently reported. Of these agents, 3 (infliximab, adalimumab, and etanercept) were formally evaluated in phase III psoriasis studies, leading to their indication for the treatment of moderate to severe psoriasis. Results of the skin responses (PASI 75) in the pivotal phase III studies on psoriasis and PsA (secondary end point) as well as the American College of Rheumatology (ACR) 20 response in PsA are summarized for the 5 different anti-TNF agents in Table 1 .
| TNF-blocker | Psoriasis Trials | PsA Trials | |||
|---|---|---|---|---|---|
| Dose | PASI 75 (%) | Dose | PASI 75 (%) | ACR 20 (%) | |
| Etanercept | 25 mg biw | 34 (wk 12) | 25 mg biw | 26 (wk 12) | 73 |
| 50 mg biw | 49 (wk 12) | — | — | — | |
| Infliximab | 5 mg/kg | 80 (wk 10) | 5 mg/kg | 64 (wk 14) | 58 |
| Adalimumab | 40 mg q2w | 71 (wk 16) | 40 mg q2w | 49 (wk 12) | 58 |
| Golimumab | — | — | 50 mg q4w | 40 (wk 14) | 51 |
| Certolizumab | — | — | 200 mg q2w | 47 (wk 12) | 58 |
Despite the fact that there are no head-to-head comparisons for any of the TNF-blockers, remarkable similarities are observed in the percentage of patients that experience at least a PASI 75 response when exposed to a monoclonal antibody targeting TNF. With the etanercept dosage classically used in rheumatology (50 mg SC [subcutaneously] weekly), a lower percentage of PASI 75 responders were observed both in the pivotal psoriasis and PsA trials. For all anti-TNF agents, the percentage of patients with at least a 75% improvement of the PASI score continues to improve with longer treatment (with a plateau usually being reached at week 24). Infliximab (chimeric) and adalimumab (fully human) are 2 monoclonal antibodies that bind specifically to soluble and membrane-bound TNF. They are currently approved for the treatment of psoriasis. Infliximab is administered intravenously at a dosage of 5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks. Patients are less likely to develop antibodies against infliximab if they are continuously treated rather than on an as-needed basis; also, clinical responses are better maintained with continuous compared with intermittent therapy. Infliximab is remarkable for the rapidity of clinical response. However, loss of efficacy may occur over time. Some dermatologists prescribe low-dose methotrexate concurrently with the goal of decreasing the formation of antibodies against infliximab and, hence, maintaining clinical efficacy over time. The dosing regimen for adalimumab in psoriasis is slightly different from the conventional dosage used in rheumatologic indications and consists of 80 mg given subcutaneously the first week, followed by 40 mg given the next week, and then every 2 weeks thereafter. Rebound does not typically occur when adalimumab is discontinued; however, skin clearance is better maintained with continuous use. Etanercept is a recombinant human TNF-alpha receptor (p75) protein fused with the Fc portion of immunoglobulin G1 (IgG1). The dosing of etanercept differs in psoriasis compared with its other indications. The approved regimen is 50 mg given subcutaneously twice weekly for the first 12 weeks followed by 50 mg weekly thereafter. Dosing is continuous. Some patients showed a loss of clinical response after 12 weeks when the dose was reduced from 50 mg twice weekly to 50 mg once weekly. Contrary to rheumatoid and PsA whereby TNF inhibitors, including etanercept, are often used in combination with methotrexate, all clinical studies in psoriasis have been performed with etanercept as a monotherapy. Continuous and interrupted etanercept therapy was effective, with greater improvements observed in the continuous arm at week 24. Most patients regained their response after the reinitiation of etanercept.
Ustekinumab
IL-12 and IL-23 have important roles in the pathophysiology of psoriasis. Ustekinumab is a human monoclonal antibody with high affinity for the p40 subunit of IL-12 and IL-23. The drug is indicated for the treatment of psoriasis. Two large, double-blind, placebo-controlled, phase III studies (Phoenix 1 and 2) in patients with moderate to severe psoriasis were conducted in parallel in the United States and Europe. The primary outcome in both studies was PASI 75 at week 12. Combining the results of both studies (including almost 2000 patients with psoriasis), a PASI 75 response at week 12 was observed in 66.7% of the ustekinumab 45-mg group (administered subcutaneously at week 0 and 4), 75.7% of the ustekinumab 90-mg dosage group, and only 3.7% of the placebo group ( P <.0001 for both ustekinumab groups vs placebo). Ustekinumab is currently the only drug for which a randomized, active-controlled, parallel, 3-arm study (ACCEPT [Active Comparator (CNTO1275/Enbrel) Psoriasis Trial] trial) was performed; ustekinumab 45 and 90 mg, respectively, was compared with etanercept 50 mg twice weekly. PASI 75 at week 12 was achieved by 56.8% of patients in the etanercept group compared with 67.5% ( P =.012) and 73.8% ( P <.001) in the ustekinumab 45- and 90-mg group, respectively.
Based on a successful phase II, double-blind, randomized, placebo-controlled study of ustekinumab in patients with active PsA (42.1% of patients in the active treatment group experienced an ACR 20 response at week 12 compared with only 14.3% in the placebo-dosed cohort), a large phase III study was designed for which preliminary results were recently reported at the EULAR 2012 meeting. Patients with active PsA (n = 615) were randomized to ustekinumab 45 mg, 90 mg, or placebo at weeks 0, 4, and every 12 weeks thereafter. A significantly greater proportion of ustekinumab patients (42.4% and 49.5% for ustekinumab 45 and 90 mg, respectively) had ACR 20 response at week 24 compared with placebo (22.8%; P <.001). Enthesitis and dactylitis also improved significantly in the active treated group. Currently, the drug is also under investigation for the treatment of AS (Ustekinumab for the Treatment of Patients with Active Ankylosing Spondylitis, which is a 28-week, prospective, open-label, proof-of-concept study; ClinicalTrials.gov identifier: NCT01330901 ). Ustekinumab also induced a clinical response in patients with moderate to severe Crohn disease.
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